PARP inhibitors as P-glyoprotein substrates

The cytotoxicity of PARP inhibitors olaparib, veliparib, and CEP-8983 were investigated in two P-glycoprotein (P-gp) overexpressing drug-resistant cell models (IGROVCDDP and KB-8-5-11). IGROVCDDP and KB-8-5-11 were both resistant to olaparib and resistance was reversible with the P-gp inhibitors elacridar, zosuquidar, and valspodar. In contrast, the P-gp overexpressing models were not resistant to veliparib or CEP-8983. Olaparib and veliparib did not induce protein expression of P-gp in IGROVCDDP or KB-8-5-11 at doses that successfully inhibit PARP. Olaparib therefore appears to be a P-gp substrate. Veliparib and CEP-8983 do not appear to be substrates. Veliparib and CEP-8983 may therefore be more useful in combined chemotherapy regimens with P-gp substrates and may be active in platinum and taxane-resistant ovarian cancer

Microbial diversity and biogeography in Arctic soils

Microorganisms dominate terrestrial environments in the polar regions and Arctic soils are known to harbour significant microbial diversity, far more diverse and numerous in the region than was once thought. Furthermore, the geographic distribution and structure of Arctic microbial communities remains elusive, despite their important roles in both biogeochemical cycling and in the generation and decomposition of climate active gases. Critically, Arctic soils are estimated to store over 1500 Pg of carbon and thus, have the potential to generate positive feedback within the climate system. As the Arctic region is currently undergoing rapid change, the likelihood of faster release of greenhouse gases such as CO2 , CH4 and N2 O is increasing. Understanding the microbial communities in the region, in terms of their diversity, abundance and functional activity, is key to producing accurate models of greenhouse gas release. This review brings together existing data to determine what we know about microbial diversity and biogeography in Arctic soils

The continuity of effect of schizophrenia polygenic risk score and patterns of cannabis use on transdiagnostic symptom dimensions at first-episode psychosis: findings from the EU-GEI study.

Diagnostic categories do not completely reflect the heterogeneous expression of psychosis. Using data from the EU-GEI study, we evaluated the impact of schizophrenia polygenic risk score (SZ-PRS) and patterns of cannabis use on the transdiagnostic expression of psychosis. We analysed first-episode psychosis patients (FEP) and controls, generating transdiagnostic dimensions of psychotic symptoms and experiences using item response bi-factor modelling. Linear regression was used to test the associations between these dimensions and SZ-PRS, as well as the combined effect of SZ-PRS and cannabis use on the dimensions of positive psychotic symptoms and experiences. We found associations between SZ-PRS and (1) both negative (B = 0.18; 95%CI 0.03-0.33) and positive (B = 0.19; 95%CI 0.03-0.35) symptom dimensions in 617 FEP patients, regardless of their categorical diagnosis; and (2) all the psychotic experience dimensions in 979 controls. We did not observe associations between SZ-PRS and the general and affective dimensions in FEP. Daily and current cannabis use were associated with the positive dimensions in FEP (B = 0.31; 95%CI 0.11-0.52) and in controls (B = 0.26; 95%CI 0.06-0.46), over and above SZ-PRS. We provide evidence that genetic liability to schizophrenia and cannabis use map onto transdiagnostic symptom dimensions, supporting the validity and utility of the dimensional representation of psychosis. In our sample, genetic liability to schizophrenia correlated with more severe psychosis presentation, and cannabis use conferred risk to positive symptomatology beyond the genetic risk. Our findings support the hypothesis that psychotic experiences in the general population have similar genetic substrates as clinical disorders

The continuity of effect of schizophrenia polygenic risk score and patterns of cannabis use on transdiagnostic symptom dimensions at first-episode psychosis: findings from the EU-GEI study

Abstract: Diagnostic categories do not completely reflect the heterogeneous expression of psychosis. Using data from the EU-GEI study, we evaluated the impact of schizophrenia polygenic risk score (SZ-PRS) and patterns of cannabis use on the transdiagnostic expression of psychosis. We analysed first-episode psychosis patients (FEP) and controls, generating transdiagnostic dimensions of psychotic symptoms and experiences using item response bi-factor modelling. Linear regression was used to test the associations between these dimensions and SZ-PRS, as well as the combined effect of SZ-PRS and cannabis use on the dimensions of positive psychotic symptoms and experiences. We found associations between SZ-PRS and (1) both negative (B = 0.18; 95%CI 0.03–0.33) and positive (B = 0.19; 95%CI 0.03–0.35) symptom dimensions in 617 FEP patients, regardless of their categorical diagnosis; and (2) all the psychotic experience dimensions in 979 controls. We did not observe associations between SZ-PRS and the general and affective dimensions in FEP. Daily and current cannabis use were associated with the positive dimensions in FEP (B = 0.31; 95%CI 0.11–0.52) and in controls (B = 0.26; 95%CI 0.06–0.46), over and above SZ-PRS. We provide evidence that genetic liability to schizophrenia and cannabis use map onto transdiagnostic symptom dimensions, supporting the validity and utility of the dimensional representation of psychosis. In our sample, genetic liability to schizophrenia correlated with more severe psychosis presentation, and cannabis use conferred risk to positive symptomatology beyond the genetic risk. Our findings support the hypothesis that psychotic experiences in the general population have similar genetic substrates as clinical disorders

Cognitive behavioural therapy for the treatment of schizophrenia spectrum disorders: an umbrella review of meta-analyses of randomised controlled trialsResearch in context

Summary: Background: Cognitive behavioural therapy (CBT) forms the standard psychotherapy for schizophrenia spectrum disorders (SSD). We aimed to summarize and evaluate the evidence on the effectiveness of CBT for SSD. Methods: In this umbrella review, we searched PubMed, Embase, Cochrane Database, and PsychInfo, for meta-analyses of randomised controlled trials (RCTs) of CBT in SSD published between database inception up to Aug 18, 2023. Inclusion criteria were RCTs investigating individually provided CBT in a population of patients with SSD, compared to either standard care, treatment as usually, or any other psychosocial therapies. No restrictions concerning follow-up or language were applied. We used the “assessment of multiple systematic reviews” (AMSTAR-2) appraisal checklist for the evaluation of methodological quality of meta-analysis. We extracted summary metrics from eligible studies in duplicate. The strength of evidence was classified by the sample size, p-value, excess significance bias, prediction intervals, significance of largest study, and heterogeneity. The strength of evidence was ranked according to established criteria as: convincing, highly suggestive, suggestive, weak, or not significant. Primary outcomes were general psychopathology, positive and negative symptoms. This study is registered in PROSPERO, CRD42022334671. Findings: We found 26 eligible meta-analyses, of which 16 meta-analyses provided sufficient data. Using the AMSTAR-2, we found limitations in details concerning the selection of study design, quality of the search and reporting of funding in included meta-analyses. A minority of 42.9% of the comparisons showed a significant result in favor of CBT; 57.1% were non-significant with no convincing or highly suggestive evidence. Suggestive evidence was found in favor of CBT for general psychopathology (6.2%, N = 34 RCTs, effect size (ES) = −0.33 (−0.47; −0.19), I2 = 67.93), delusions (16.7%, N = 27, ES = 0.36 (0.22; 0.51), I2 = 50.47), and hallucinations (33.3%, N = 28, ES = 0.32 (0.19; 0.46), I2 = 45.14) at the end of treatment (EoT). Weak (N = 34 RCTs, ES = −0.13 (−0.24; −0.02), I2 = 51.28), or non-significant evidence (N = 28 RCTs, ES = 0.12 (−0.03; 0.27) I2 = 64.63) was found for negative symptoms at EoT. At longer follow-up, evidence became weak or non-significant. Interpretation: Findings suggest that the effectiveness of CBT on general and positive symptoms in SSD at EoT was small to medium, while we found inconsistent evidence for a sustainable effect. CBT has no convincing impact on other relevant outcomes. Guidelines may use these results to specify their recommendations. Funding: None

BioSimGrid: grid-enabled biomolecular simulation data storage and analysis

In computational biomolecular research, large amounts of simulation data are generated to capture the motion of proteins. These massive simulation data can be analysed in a number of ways to reveal the biochemical properties of the proteins. However, the legacy way of storing these data (usually in the laboratory where the simulations have been run) often hinders a wider sharing and easier cross-comparison of simulation results. The data is commonly encoded in a way specific to the simulation package that produced the data and can only be analysed with tools developed specifically for that simulation package. The BioSimGrid platform seeks to provide a solution to these challenges by exploiting the potential of the Grid in facilitating data sharing. By using BioSimGrid either in a scripting or web environment, users can deposit their data and reuse it for analysis. BioSimGrid tools manage the multiple storage locations transparently to the users and provide a set of retrieval and analysis tools for processing the data in a convenient and efficient manner. This paper details the usage and implementation of BioSimGrid usinga combination of commercial databases, the Storage Resource Broker and Python scripts, gluing the building blocks together. It introduces a case study of how BioSimGrid can be used for better storage, retrieval and analysis of biomolecular simulation data

Draft genome sequence analysis of a Pseudomonas putida W15Oct28 strain with antagonistic activity to Gram-positive and Pseudomonas sp. pathogens.

Pseudomonas putida is a member of the fluorescent pseudomonads known to produce the yellow-green fluorescent pyoverdine siderophore. P. putida W15Oct28, isolated from a stream in Brussels, was found to produce compound(s) with antimicrobial activity against the opportunistic pathogens Staphylococcus aureus, Pseudomonas aeruginosa, and the plant pathogen Pseudomonas syringae, an unusual characteristic for P. putida. The active compound production only occurred in media with low iron content and without organic nitrogen sources. Transposon mutants which lost their antimicrobial activity had the majority of insertions in genes involved in the biosynthesis of pyoverdine, although purified pyoverdine was not responsible for the antagonism. Separation of compounds present in culture supernatants revealed the presence of two fractions containing highly hydrophobic molecules active against P. aeruginosa. Analysis of the draft genome confirmed the presence of putisolvin biosynthesis genes and the corresponding lipopeptides were found to contribute to the antimicrobial activity. One cluster of ten genes was detected, comprising a NAD-dependent epimerase, an acetylornithine aminotransferase, an acyl CoA dehydrogenase, a short chain dehydrogenase, a fatty acid desaturase and three genes for a RND efflux pump. P. putida W15Oct28 genome also contains 56 genes encoding TonB-dependent receptors, conferring a high capacity to utilize pyoverdines from other pseudomonads. One unique feature of W15Oct28 is also the presence of different secretion systems including a full set of genes for type IV secretion, and several genes for type VI secretion and their VgrG effectors

Phylogeny of TonB-dependent receptors.

<p>Neighbor joining tree based on the alignment of amino acid sequences of the 56 TonB dependent receptors (TBDR) detected in the genome of W15oct28 (green font) and a selection of known ferric-pyoverdine receptors from different sequenced Pseudomonas genomes (black font). W15oct28 TBDRs that are regulated through sigma-anti-sigma factors are indicated with a red node. Grey surface indicates part of the tree that contains all ferric-pyoverdine receptors that form a separate cluster.</p

Fractionation of the antagonistic activity by HPLC.

<p>HPCL fractionation of a crude extract from a culture supernatant of <i>P. putida</i> W15Oct28 grown in M9-glucose medium: A, chromatography of crude extraction of W15Oct28 cultured in M9 minimal medium for 48 hours; B, chromatography of crude extraction of W15Oct28 cultured in M9 minimal medium for 48 hours plus 5 days stay at 6°C. The yield of fraction 1 and 4 were increased with longer time of cultivation. Fractions 1 to 4 were spotted on an agar plate inoculated with <i>P. aeruginosa</i> PAO1 (upper left, fraction 1, upper right, fraction 2, lower left, fraction 3, lower right, fraction 4). The green line represents the acetonitrile gradient.</p